Fragrances are of great interest especially in the field of cosmetics and also laundry and cleaning detergents. Fragrances of natural origin are mostly expensive, often limited in their available amount and, on account of fluctuations in environmental conditions, are also subject to variations in their content, purity etc. It is therefore of great interest to be able to replace, at least partially, fragrances of natural origin with synthetically obtainable substances.
Synthetic 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols, such as 1-(2,6,6-trimethyl-cyclohexyl)-pentan-3-ol and 1-(2,6,6-trimethylcyclohexyl)-hexan-3-ol, are valuable aroma chemicals. In particular 1-(2,6,6-trimethylcyclohexyl)-hexan-3-ol has found widespread use in products and compositions, which typically comprise at least one aroma compound, such as in laundry and fabric detergents, soaps, perfumes and the like.
Several methods for the preparation of 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols are known in the state of the art.
Generally, 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols are obtained via an aldol condensation of citral (3,7-dimethylocta-2,6-dienal) with the corresponding 2-alkanones in the presence of a base, followed by the acid catalyzed cyclization of the corresponding aldol condensation products. The obtained 1-(2,6,6-trimethylcyclohexenyl)-1-alken-3-ones are then hydrogenated to the desired 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols in known manner.
DE2455761 and EP1400503 for example describe a process for the preparation of 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols containing a high proportion of trans isomers by hydrogenating the corresponding 1-(2,6,6-trimethylcyclohexenyl)-1-alken-3-ones using Raney nickel.
EP10062771 describes a process for the preparation of 1-(2,6,6-trimethylcyclohexyl)-alkan-3-ols with a high content of trans isomers by hydrogenation of the corresponding 1-(2,6,6-trimethylcyclohexenyI)-1-alken-3-ones using ruthenium catalysts.
1-(2,6,6-Trimethylcyclohexyl)-hexan-3-ol for example is typically obtained following known procedures, e.g. described by Hibbert et al., J. Am. Chem. Soc., 1924, Vol. 46, pp. 119-130, and by Naves et al., Helv. Chim. Acta, 1943, Vol. 26, pp. 2151-2165, which comprises an aldol condensation of citral (3,7-dimethylocta-2,6-dienal) with 2-pentanone in the presence of a base, followed by an acid catalyzed cyclization and the subsequent hydrogenation of the obtained 1-(2,6,6-trimethylcyclohexenyl)-1-hexen-3-one. In an alternative approach, citral is first cyclized to cyclocitral (2,6,6-Trimethyl-1-cyclohexene-1-carboxaldehyde), then condensed with 2-pentanone and subsequently hydrogenated. A detailed overview of the technical synthesis of 1-(2,6,6-trimethylcyclohexyl)-hexan-3-ol starting from citral can be found in H. Surburg and J. Panten, Common Flavor and Fragrance Materials, 4th edition, page 85 and the references cited therein.
EP1749810 A1 describes the preparation of 1-(2,2,6-trimethyl cyclohexyl)-hexan-3-ol with at least 30 wt. % of the corresponding trans-isomers by catalytically hydrogenating 1-(2,6,6-trimethylcyclohexenyI)-1-hexen-3-one in the presence of a rhodium-catalyst.
U.S. Pat. No. 4,623,750 and EP0118809 A2 describe a process for the production of 1-(2,6,6-trimethylcyclohexyl)-hexan-3-ol, where cyclocitral is first hydrogenated to dihydro-cyclocitral and then condensed with 2-pentanone and finally again hydrogenated.
All these methods are based on readily available citral as bulk material, but need to employ expensive 2-alkanones, such as 2-pentanone, or other costly speciality chemicals.
Surprisingly, no method is described for the production of 1-(2,6,6-trimethylcyclohexyl)-hexan-3-ol, which directly starts from the bulk chemicals ionones and acetaldehyde. In general, the use of ionones for aldol reactions with aldehydes is rarely described, and if so, then very strong bases, as e.g. butyllithium (BuLi), are used.
Valla et al., Tetrahedron Letters, 2005, Vol. 46, (39), pp. 6671-6674, describe the reaction of beta-ionone with N,N-dimethylformamide dimethylacetal (DMFDMA) by refluxing the two reagents for several hours. The resulting enaminone is further transferred to 1-(2,6,6-trimethylcyclohexen-1-yl)alkan-1,4-dien-3-ones using alkyllithium or alkylmagnesiumhalides.
Kepler et al., J. Med. Chem., 1988, Vol. 31, pp. 713-716, describe the reaction of beta-ionone with acetaldehyde using very strong bases, i.e. buthyllithium and diisopropylamine. The reaction is performed at −78° C. using THF as the solvent. Apart from the fact that the condensation reaction is performed in an organic solvent in the presence of very strong bases, which are critical for use in large scale production, Kepler et al. do not describe the further conversion of the corresponding condensation product to 1-(2,6,6-trimethylcyclohexen-1-yl)-hexa-1,4-dien-3-one and/or 1-(2,6,6-trimethylcyclo-hexyl)-hexan-3-ol.